Astrocytic TIMP-1 regulates production of Anastellin, an inhibitor of oligodendrocyte differentiation and FTY720 responses.

Astrocyte activation is associated with neuropathology and the production of tissue inhibitor of metalloproteinase-1 (TIMP1). TIMP1 is a pleiotropic extracellular protein that functions both as a protease inhibitor and as a growth factor. Astrocytes that lack expression of Timp1 do not support rat oligodendrocyte progenitor cell (rOPC) differentiation, and adult global Timp1 knockout (Timp1KO) mice do not efficiently remyelinate following a demyelinating injury. Here, we performed an unbiased proteomic analysis and identified a fibronectin-derived peptide called Anastellin (Ana) that was unique to the Timp1KO astrocyte secretome. Ana was found to block rOPC differentiation in vitro and enhanced the inhibitory influence of fibronectin on rOPC differentiation. Ana is known to act upon the sphingosine-1-phosphate receptor 1, and we determined that Ana also blocked the pro-myelinating effect of FTY720 (or fingolimod) on rOPC differentiation in vitro. Administration of FTY720 to wild-type C57BL/6 mice during MOG35-55-experimental autoimmune encephalomyelitis ameliorated clinical disability while FTY720 administered to mice lacking expression of Timp1 (Timp1KO) had no effect. Analysis of Timp1 and fibronectin (FN1) transcripts from primary human astrocytes from healthy and multiple sclerosis (MS) donors revealed lower TIMP1 expression was coincident with elevated FN1 in MS astrocytes. Last, analyses of proteomic databases of MS samples identified Ana peptides to be more abundant in the cerebrospinal fluid (CSF) of human MS patients with high disease activity. A role for Ana in MS as a consequence of a lack of astrocytic TIMP-1 production could influence both the efficacy of fingolimod responses and innate remyelination potential in the MS brain.

Defective sphingosine 1-phosphate receptor 1 (S1P1) phosphorylation exacerbates TH17-mediated autoimmune neuroinflammation.

Sphingosine 1-phosphate (S1P) signaling regulates lymphocyte egress from lymphoid organs into systemic circulation. The sphingosine phosphate receptor 1 (S1P1) agonist FTY-720 (Gilenya) arrests immune trafficking and prevents multiple sclerosis (MS) relapses. However, alternative mechanisms of S1P-S1P1 signaling have been reported. Phosphoproteomic analysis of MS brain lesions revealed S1P1 phosphorylation on S351, a residue crucial for receptor internalization. Mutant mice harboring an S1pr1 gene encoding phosphorylation-deficient receptors (S1P1(S5A)) developed severe experimental autoimmune encephalomyelitis (EAE) due to autoimmunity mediated by interleukin 17 (IL-17)-producing helper T cells (TH17 cells) in the peripheral immune and nervous system. S1P1 directly activated the Jak-STAT3 signal-transduction pathway via IL-6. Impaired S1P1 phosphorylation enhances TH17 polarization and exacerbates autoimmune neuroinflammation. These mechanisms may be pathogenic in MS.

Comparative Analyses and Ablation Efficiency of Thulium Fiber Laser by Stone Composition.

PURPOSE: There are limited data on ablation effects of thulium fiber laser (TFL) settings with varying stone composition. Similarly, little is known surrounding the photothermal effects of TFL lithotripsy regarding the chemical and structural changes after visible char formation. We aim to understand the TFL's ablative efficiency across various stone types and laser settings, while simultaneously investigating the photothermal effects of TFL lithotripsy. MATERIALS AND METHODS: Human specimens of calcium oxalate monohydrate, calcium oxalate dihydrate, uric acid, struvite, cystine, carbonate apatite, and brushite stones were ablated using 13 prespecified settings with the Coloplast TFL Drive. Pre- and postablation mass, ablation time, and total energy were recorded. Qualitative ablative observations were recorded at 1-minute intervals with photographs and gross description. Samples were analyzed with Fourier-transform infrared spectroscopy pre- and postablation and electron microscopy postablation to assess the photothermal effects of TFL. RESULTS: Across all settings and stone types, 0.05 J × 1000 Hz was the best numerically efficient ablation setting. When selected for more clinically relevant laser settings (ie, 10-20 W), 0.2 J × 100 Hz, short pulse was the most numerically efficient setting for calcium oxalate dihydrate, cystine, and struvite stones. Calcium oxalate monohydrate ablated with the best numerical efficiency at 0.4 J × 40 Hz, short pulse. Uric acid and carbonate apatite stones ablated with the best numerical efficiency at 0.3 J × 60 Hz, short pulse. Brushite stones ablated with the best numerical efficiency at 0.5 J × 30 Hz, short pulse. Pulse duration impacted ablation effectiveness greatly with 6/8 (75%) of inadequate ablations occurring in medium or long pulse settings. The average percent of mass lost during ablation was 57%; cystine stones averaged the highest percent mass lost at 71%. Charring was observed in 36/91 (40%) specimens. Charring was most often seen in uric acid, cystine, and brushite stones across all laser settings. Electron microscopy of char demonstrated a porous melting effect different to that of brittle fracture. Fourier-transform infrared spectroscopy of brushite char demonstrated a chemical composition change to amorphous calcium phosphate. CONCLUSIONS: We describe the optimal ablation settings based on stone composition, which may guide urologists towards more stone-specific care when using thulium laser for treating renal stones (lower energy settings would be safer for ureteral stones). For patients with unknown stone composition, lasers can be preset to target common stone types or adjusted based on visual cues. We recommend using short pulse for all TFL lithotripsy of calculi and altering the settings based on visual cues and efficiency to minimize the charring, an effect which can make the stone refractory to further dusting and fragmentation.

Comparison of transvaginal ultrasound utilization between radiology and point of care ultrasound in first trimester pregnancy.

BACKGROUND: Transvaginal (TVUS) and transabdominal ultrasound (TAUS) are both utilized in the evaluation of early pregnancy patients. While many practitioners using point of care ultrasound (POCUS) will generally not pursue TVUS in cases where an intrauterine pregnancy (IUP) is visualized on TAUS, this may not be true in Radiology performed ultrasound. OBJECTIVES: To evaluate for differences in transvaginal ultrasound (TVUS) utilization between Radiology performed (RP) ultrasound and point of care ultrasound (POCUS) by Emergency Department (ED) physicians in early pregnancy patients. Secondarily, to assess length of stay (LOS) differences and the impact of specialized emergency ultrasound training on TVUS utilization. METHODS: This was a retrospective study at a single academic ED. Study population was all ED patients who underwent first trimester ultrasound during the one year period of March 1, 2021 to February 28, 2022. Variables evaluated were chief complaint, gestational age, LOS, TAUS and TVUS utilization, ultrasound findings, and ultrasound specialty training of the ED physician. RESULTS: There were 133 cases of POCUS ultrasound and 254 cases of RP ultrasound. All cases had TAUS imaging performed. Median LOS for patients when POCUS was utilized was 207 min (IQR 151-294) and 258 min (IQR 208-328) for those only using RP ultrasound, p ≤ 0.001. In the POCUS cohort, 38% (95% CI 30%-46%) received TVUS, while 94% received TVUS in the RP cohort (95% CI 90%-96%), p ≤ 0.001. Patients seen by ED faculty with ultrasound specialty training had TVUS 53% of the time (95% CI 41%-65%), while those seen by other ED faculty had TVUS 79% (95% CI 74%-83%) of the time, p = 0.035. CONCLUSION: POCUS in early pregnancy is associated with a significant reduction in TVUS usage. We suspect that POCUS users elect not to pursue TVUS after an IUP is identified on TAUS, while technicians perform protocol-based TVUS irrespective of TAUS findings. Patients seen by ultrasound trained ED physicians are less likely to receive TVUS.

On the use of simulation in robotics: Opportunities, challenges, and suggestions for moving forward.

The last five years marked a surge in interest for and use of smart robots, which operate in dynamic and unstructured environments and might interact with humans. We posit that well-validated computer simulation can provide a virtual proving ground that in many cases is instrumental in understanding safely, faster, at lower costs, and more thoroughly how the robots of the future should be designed and controlled for safe operation and improved performance. Against this backdrop, we discuss how simulation can help in robotics, barriers that currently prevent its broad adoption, and potential steps that can eliminate some of these barriers. The points and recommendations made concern the following simulation-in-robotics aspects: simulation of the dynamics of the robot; simulation of the virtual world; simulation of the sensing of this virtual world; simulation of the interaction between the human and the robot; and, in less depth, simulation of the communication between robots. This Perspectives contribution summarizes the points of view that coalesced during a 2018 National Science Foundation/Department of Defense/National Institute for Standards and Technology workshop dedicated to the topic at hand. The meeting brought together participants from a range of organizations, disciplines, and application fields, with expertise at the intersection of robotics, machine learning, and physics-based simulation.

Indications for and results of renal autotransplantation.

PURPOSE OF REVIEW: To understand the indications and outcomes of renal autotransplantation, and when to consider this unique procedure for patients. RECENT FINDINGS: Renal autotransplantation confers acceptably low rates of graft failure and prevents need for long-term dialysis. Renal autotransplantation remains an important management strategy in very select patients for complex renovascular disease, ureteral stricture disease, ureteral trauma, upper urinary tract urothelial carcinoma, renal cell carcinoma, and Loin-Pain Hematuria Syndrome. With advancements in minimally invasive procedures, the application of renal autotransplantation for refractory stone disease is rare but exists. Robot-assisted laparoscopic renal autotransplantation demonstrates reproducible graft success and complication rates with improved perioperative outcomes (ex. hospital length of stay) - though comparative studies are lacking. Patients would benefit from a multidisciplinary approach from renal transplant surgeons, vascular surgeons, urologists, nephrologists, dieticians, pain management providers, social workers, and psychiatrists. SUMMARY: In experienced hands, renal autotransplantation is a reasonable treatment approach for complex and refractory renal vascular disease, Loin-Pain Hematuria Syndrome, ureteral strictures and trauma, upper urinary tract malignancy, and stone disease in highly select patients.

The role of transcorporal cuff placement in high-risk and ultra-high-risk patients: are they actually helpful?

PURPOSE: To assess the incidence of artificial urinary sphincter (AUS) explant in high-risk patients and to evaluate the relationship between transcorporal cuff (TCC) placement and explant risk in this population. METHODS: We retrospectively reviewed all AUS insertions performed on high-risk patients by a single surgeon from 2010 to 2020. "High-risk" was defined as having ≥ 1 urethral risk factor: pelvic radiation, urethroplasty, recalcitrant urethral/bladder neck stenosis, urethral stenting, or previous AUS erosion/infection. Patients with ≥ 2 factors were "ultra-high-risk." Time-to-event analyses were used to assess all-cause-, infection/erosion-related-, and mechanical failure-related explant-free survival. Subgroup analyses were performed for patients with a history of radiation and urethral dissection. RESULTS: The final cohort included 68 men, mean age of 67 years (SD 11), and 77 AUS cuffs. Mean follow-up was 32 months (IQR 6-50). 29% of cuffs (n = 22) were transcorporal. 32 cuffs (42%) were explanted. All-cause explant-free survival was 64% at 1 year and 52% at 2 years. Classification as "ultra-high-risk" was not associated with explant risk (all p-values > 0.05). TCC placement was associated with an increased risk of explant for infection/erosion across all patients (HR 2.74, p = 0.03) and in radiated patients (n = 50; HR 4.1, p = 0.04), but not in patients with prior urethral dissection (n = 52; HR 1.98, p = 0.21). CONCLUSION: High-risk patients have a high rate of AUS explant and TCC placement may not be protective in this population. TCC placement was associated with an increased risk of infection/erosion in radiated patients, but not in those with a history of open urethral surgery.

The State of Urotrauma Education Among Residency Programs in the United States: A Systematic Review and Meta-Analysis.

PURPOSE OF REVIEW: Management of urotrauma is a crucial part of a urologist's knowledge and training. We therefore sought to understand the state of urotrauma education in the United States. RECENT FINDINGS: Using themes of "Urotrauma" and "Education," we performed a systematic review and meta-analysis by searching for studies in MEDLINE, all Cochrane libraries, EMBASE, BIOSIS, Scopus, and Web of Science through May 2023. The primary outcome was the pooled rate of urology trainee and program director attitudes toward urotrauma education. Secondary outcomes involved a descriptive summary of existing urotrauma curricula and an assessment of factors affecting urotrauma exposure. Of 12,230 unique records, 11 studies met the final eligibility criteria, and we included 2 in the meta-analysis. The majority of trainees and program directors reported having level 1 trauma center rotations (range 88-89%) and considered urotrauma exposure as an important aspect of residency education (83%, 95% CI 76-88%). Despite possible increases in trainee exposure to Society of Genitourinary Reconstructive Surgeons (GURS) faculty over the preceding decade, nearly a third of trainees and program directors currently felt there remained inadequate exposure to urotrauma during training (32%, 95% CI 19-46%). Factors affecting urotrauma education include the limited exposure to GURS-trained faculty and clinical factors such as case infrequency and non-operative trauma management. Urology resident exposure to urotrauma is inadequate in many training programs, underscoring the potential value of developing a standardized curriculum to improve urotrauma education for trainees. Further investigation is needed to characterize this issue and to understand how it impacts trainee practice readiness.

POINT-OF-CARE ULTRASOUND FOR GUIDANCE OF CLOSED REDUCTION OF FIFTH METACARPAL NECK (BOXER'S) FRACTURE.

BACKGROUND: Ultrasound has been used previously in fracture identification, analgesia delivery, and fracture reduction for patients in the emergency department. It has not been previously described as a tool for the guidance of closed fracture reduction in fifth metacarpal neck fractures ("boxer's fractures"). CASE REPORT: A 28-year-old man presented with hand pain and swelling after punching a wall. Point-of-care ultrasound revealed a significantly angulated fifth metacarpal fracture, which was confirmed with a subsequent hand x-ray study. After an ultrasound-guided ulnar nerve block, closed reduction was performed. Ultrasound was used to assess reduction and ensure improvement in bony angulation during the closed reduction attempts. Post-reduction x-ray study confirmed improved angulation and adequate alignment. Why Should an Emergency Physician Be Aware of This? Point-of-care ultrasound has previously had efficacy in fracture diagnosis and anesthesia delivery for fifth metacarpal fractures. Ultrasound can also be used at the bedside to assist in the determination of adequate fracture reduction when performing closed reduction of a boxer's fracture.

Cross-Referencing Self-Training Network for Sound Event Detection in Audio Mixtures.

Sound event detection is an important facet of audio tagging that aims to identify sounds of interest and define both the sound category and time boundaries for each sound event in a continuous recording. With advances in deep neural networks, there has been tremendous improvement in the performance of sound event detection systems, although at the expense of costly data collection and labeling efforts. In fact, current state-of-the-art methods employ supervised training methods that leverage large amounts of data samples and corresponding labels in order to facilitate identification of sound category and time stamps of events. As an alternative, the current study proposes a semi-supervised method for generating pseudo-labels from unsupervised data using a student-teacher scheme that balances self-training and cross-training. Additionally, this paper explores post-processing which extracts sound intervals from network prediction, for further improvement in sound event detection performance. The proposed approach is evaluated on sound event detection task for the DCASE2020 challenge. The results of these methods on both "validation" and "public evaluation" sets of DESED database show significant improvement compared to the state-of-the art systems in semi-supervised learning.

A phase 1 study to evaluate the safety, tolerability and pharmacokinetics of TAK-041 in healthy participants and patients with stable schizophrenia.

AIMS: TAK-041 (NBI-1065846), an orally available, investigational, small molecule agonist of GPR139, an orphan G-protein-coupled receptor, has shown promise in preclinical studies for the treatment of symptoms associated with schizophrenia. Here, we report the results from a phase 1 study to evaluate the safety, tolerability and pharmacokinetics of TAK-041 in healthy adults and exploratory efficacy assessment of TAK-041 as adjunctive therapy to antipsychotics in adults with stable schizophrenia (ClinicalTrials.gov: NCT02748694). METHODS: The study comprised 4 parts: parts 1-3 were undertaken in healthy adults and part 4 in patients with stable schizophrenia. Part 1 was a single-rising-dose study, part 2 was a multiple-rising-dose study that assessed plasma exposure and accumulation, part 3 evaluated the bioavailability of tablet formulation versus oral suspension, and part 4 was a repeat multiple-dose study in patients with stable schizophrenia. RESULTS: No serious adverse events were reported. TAK-041 had a nearly linear pharmacokinetics profile, with rapid absorption and long half-life of 170-302 hours across all doses tested. Bioavailability was similar between the tablet formulation and oral suspension, and no meaningful food effect was detected. Systemic exposure was 22-30% lower for patients with schizophrenia than for healthy volunteers. A potential signal of improvement was detected in the anxiety-depression scale of the Positive and Negative Syndrome Scale (P = .0002, not corrected for multiplicity) and the Temporal Experience of Pleasure Scale in patients with schizophrenia. CONCLUSION: TAK-041 was generally well tolerated in healthy volunteers and adults with schizophrenia. Further investigation of TAK-041 in individuals with schizophrenia is supported.

AZD8233 antisense oligonucleotide targeting PCSK9 does not prolong QT interval.

AIMS: AZD8233 is a proprotein convertase subtilisin/kexin type 9 (PCSK9) antisense oligonucleotide under development for treatment of hypercholesterolaemia. A prespecified concentration-QT analysis was performed based on data from a single ascending dose study that was prospectively designed to act as a TQT study substitute. METHODS: Subcutaneous single doses ranging from 4 to 120 mg were evaluated in 73 adult healthy male subjects. Time-matched 12-lead digital ECG and plasma concentrations (n = 15) were measured at baseline and up to 48 hours after dose in each subject. The analysis was performed using a linear mixed effect model, where change from baseline QTc (ΔQTc) was a dependent variable and time-matched AZD8233 concentration was an independent variable. RESULTS: The high clinical exposure scenario was defined as 1.7-fold the expected Cmax following an assumed therapeutic dose of 60 mg, which corresponds to AZD8233 plasma concentration of 1.39 µg/mL. Estimated placebo-corrected and baseline-adjusted QTcF interval (ΔΔQTcF) at this concentration was -2.2 ms (90% CI: -4.11, -0.28). Furthermore, the upper 90% ΔΔQTcF confidence interval was estimated to be below 10 ms at all observed concentrations. CONCLUSION: As the effect on ΔΔQTcF is below the threshold for regulatory concern (10 ms), it can be concluded that AZD8233 does not induce QTcF prolongation at the high clinical exposure scenario.

Clinical evaluation of the potential drug-drug interactions of savolitinib: Interaction with rifampicin, itraconazole, famotidine or midazolam.

AIMS: We investigated savolitinib pharmacokinetics (PK) when administered alone or in combination with rifampicin, itraconazole or famotidine, and investigated midazolam PK when administered with or without savolitinib in healthy males. METHODS: Savolitinib PK was evaluated before/after: rifampicin (600 mg once daily [QD] for 5 days); itraconazole (200 mg QD for 5 days); a single dose of famotidine (40 mg QD) 2 hours before savolitinib. Midazolam PK was evaluated before/after midazolam (1 mg QD) with or without savolitinib (600 mg QD). Each study enrolled 20, 16, 16 and 14 volunteers, respectively. Plasma samples were collected to determine the effect on PK. RESULTS: The geometric mean ratios (GMR, %) (90% confidence intervals [CIs]) for savolitinib alone and in combination for Cmax , AUC respectively, were 45.4 (41.4-49.9), 38.5 (34.2-43.3) in the rifampicin study (n = 18); 105.2 (87.7-126.3), 108.4 (96.3-122.1) in the itraconazole study (n = 16); and 78.8 (67.7-91.7), 87.4 (81.2-94.2) in the famotidine study (n = 16). The GMRs (90% CIs) for midazolam alone and in combination with savolitinib for Cmax , AUC respectively, were 84.1 (70.0-101.0), 96.7 (92.4-101.1) (n = 14). Savolitinib alone or in combination was well tolerated. CONCLUSIONS: Co-dosing of rifampicin significantly reduced exposure to savolitinib vs savolitinib alone; co-dosing of itraconazole or midazolam with savolitinib had no clinically significant effect on savolitinib or midazolam PK, respectively. Co-dosing of famotidine with savolitinib reduced exposure to savolitinib, although this was not considered clinically meaningful. No new savolitinib-related safety findings were observed.

Bioavailability of acalabrutinib suspension delivered via nasogastric tube in the presence or absence of a proton pump inhibitor in healthy subjects.

AIMS: Acalabrutinib, a selective Bruton tyrosine kinase inhibitor, is approved for the treatment of mantle cell lymphoma and chronic lymphocytic leukaemia. Many critically ill patients are unable to swallow and need oral medications to be delivered via a nasogastric (NG) tube. Furthermore, critically ill patients are typically administered proton-pump inhibitors (PPIs) to prevent stress ulcers. Concomitant administration with PPIs reduces acalabrutinib exposure and is not currently recommended. To evaluate acalabrutinib in subjects co-administered with PPIs who require NG delivery, a phase 1, open-label, randomized, crossover, single-dose study was conducted in healthy subjects. METHODS: The study assessed the relative bioavailability of an acalabrutinib suspension-in regular, degassed Coca-Cola-administered via NG tube (Acala-NG) versus the pharmacokinetics (PK) of an acalabrutinib capsule administered orally with water. In addition, the PPI effect was evaluated by comparing the PK following Acala-NG in the presence or absence of rabeprazole. RESULTS: Exposure of acalabrutinib and its active metabolite (ACP-5862) were comparable following administration of Acala-NG versus the oral capsule (Geo mean ratio, % ref [90% confidence interval, CI]: acalabrutinib AUCinf : 103 [93-113]; Cmax : 144 [120-173]). In addition, exposure was similar following administration of Acala-NG with and without a PPI (Geo mean ratio, % ref [90% CI]: acalabrutinib AUCinf : 105 [79-138]; Cmax : 95 [66-137]). No safety or tolerability concerns were observed, and all adverse events were mild and resolved without treatment. CONCLUSIONS: Acala-NG with or without a PPI is safe and well-tolerated without impeding bioavailability.

Extracellular vesicle fibrinogen induces encephalitogenic CD8+ T cells in a mouse model of multiple sclerosis.

Extracellular vesicles (EVs) are emerging as potent mediators of intercellular communication with roles in inflammation and disease. In this study, we examined the role of EVs from blood plasma (pEVs) in an experimental autoimmune encephalomyelitis mouse model of central nervous system demyelination. We determined that pEVs induced a spontaneous relapsing-remitting disease phenotype in MOG35-55-immunized C57BL/6 mice. This modified disease phenotype was found to be driven by CD8+ T cells and required fibrinogen in pEVs. Analysis of pEVs from relapsing-remitting multiple sclerosis patients also identified fibrinogen as a significant portion of pEV cargo. Together, these data suggest that fibrinogen in pEVs contributes to the perpetuation of neuroinflammation and relapses in disease.

Photoacoustic Imaging of Human Vasculature Using LED versus Laser Illumination: A Comparison Study on Tissue Phantoms and In Vivo Humans.

Vascular diseases are becoming an epidemic with an increasing aging population and increases in obesity and type II diabetes. Point-of-care (POC) diagnosis and monitoring of vascular diseases is an unmet medical need. Photoacoustic imaging (PAI) provides label-free multiparametric information of deep vasculature based on strong absorption of light photons by hemoglobin molecules. However, conventional PAI systems use bulky nanosecond lasers which hinders POC applications. Recently, light-emitting diodes (LEDs) have emerged as cost-effective and portable optical sources for the PAI of living subjects. However, state-of-art LED arrays carry significantly lower optical energy (<0.5 mJ/pulse) and high pulse repetition frequencies (PRFs) (4 KHz) compared to the high-power laser sources (100 mJ/pulse) with low PRFs of 10 Hz. Given these tradeoffs between portability, cost, optical energy and frame rate, this work systematically studies the deep tissue PAI performance of LED and laser illuminations to help select a suitable source for a given biomedical application. To draw a fair comparison, we developed a fiberoptic array that delivers laser illumination similar to the LED array and uses the same ultrasound transducer and data acquisition platform for PAI with these two illuminations. Several controlled studies on tissue phantoms demonstrated that portable LED arrays with high frame averaging show higher signal-to-noise ratios (SNRs) of up to 30 mm depth, and the high-energy laser source was found to be more effective for imaging depths greater than 30 mm at similar frame rates. Label-free in vivo imaging of human hand vasculature studies further confirmed that the vascular contrast from LED-PAI is similar to laser-PAI for up to 2 cm depths. Therefore, LED-PAI systems have strong potential to be a mobile health care technology for diagnosing vascular diseases such as peripheral arterial disease and stroke in POC and resource poor settings.

Fusion-ConvBERT: Parallel Convolution and BERT Fusion for Speech Emotion Recognition.

Speech emotion recognition predicts the emotional state of a speaker based on the person's speech. It brings an additional element for creating more natural human-computer interactions. Earlier studies on emotional recognition have been primarily based on handcrafted features and manual labels. With the advent of deep learning, there have been some efforts in applying the deep-network-based approach to the problem of emotion recognition. As deep learning automatically extracts salient features correlated to speaker emotion, it brings certain advantages over the handcrafted-feature-based methods. There are, however, some challenges in applying them to the emotion recognition problem, because data required for properly training deep networks are often lacking. Therefore, there is a need for a new deep-learning-based approach which can exploit available information from given speech signals to the maximum extent possible. Our proposed method, called "Fusion-ConvBERT", is a parallel fusion model consisting of bidirectional encoder representations from transformers and convolutional neural networks. Extensive experiments were conducted on the proposed model using the EMO-DB and Interactive Emotional Dyadic Motion Capture Database emotion corpus, and it was shown that the proposed method outperformed state-of-the-art techniques in most of the test configurations.

The impact of frequent cystoscopy on surgical care and cancer outcomes among patients with low-risk, non-muscle-invasive bladder cancer.

BACKGROUND: Surveillance recommendations for patients with low-risk, non-muscle-invasive bladder cancer (NMIBC) are based on limited evidence. The objective of this study was to add to the evidence by assessing outcomes after frequent versus recommended cystoscopic surveillance. METHODS: This was a retrospective cohort study of patients diagnosed with low-risk (low-grade Ta (AJCC)) NMIBC from 2005 to 2011 with follow-up through 2014 from the Department of Veterans Affairs. Patients were classified as having undergone frequent versus recommended cystoscopic surveillance (>3 vs 1-3 cystoscopies in the first 2 years after diagnosis). By using propensity score-adjusted models, the authors estimated the impact of frequent cystoscopy on the number of transurethral resections, the number of resections without cancer in the specimen, and the risk of progression to muscle-invasive cancer or bladder cancer death. RESULTS: Among 1042 patients, 798 (77%) had more frequent cystoscopy than recommended. In adjusted analyses, the frequent cystoscopy group had twice as many transurethral resections (55 vs 26 per 100 person-years; P < .001) and more than 3 times as many resections without cancer in the specimen (5.7 vs 1.6 per 100 person-years; P < .001). Frequent cystoscopy was not associated with time to progression or bladder cancer death (3% at 5 years in both groups; P = .990). CONCLUSIONS: Frequent cystoscopy among patients with low-risk NMIBC was associated with twice as many transurethral resections and did not decrease the risk for bladder cancer progression or death, supporting current guidelines.

No Dose Adjustment for Isavuconazole Based on Age or Sex.

This phase 1, open-label, single-dose, parallel-group study evaluated the pharmacokinetics (PK) of isavuconazole after a single oral dose of the prodrug isavuconazonium sulfate in healthy nonelderly (age, 18 to 45 years) and elderly (age, ≥65 years) males and females. Overall, 48 subjects were enrolled in the study (n = 12 each in groups of nonelderly males and females and elderly males and females). All subjects received a single oral dose of 372 mg of isavuconazonium sulfate (equivalent to 200 mg isavuconazole). PK samples were collected for analysis of isavuconazole plasma concentrations from the predose time point up to 336 h postdose. Data were analyzed using population pharmacokinetic (PPK) analysis. The resulting PPK model included two compartments with Weibull absorption function as well as interindividual variability with respect to clearance, intercompartment clearance, volumes of central and peripheral compartments, and two Weibull absorption parameters, RA and KAMAX. The PPK analysis showed that elderly females had the highest exposure versus males (ratio of total area under the time-concentration curve [AUC], 138; 90% confidence interval [CI], 118 to 161) and versus nonelderly females (ratio of AUC, 147; 90% CI, 123 to 176). Higher exposures in elderly females were not associated with significant toxicity or treatment-emergent adverse events, as measured in this study. No dose adjustments appear to be necessary based on either age group or sex even with an increase in exposure for elderly females. (This study has been registered at ClinicalTrials.gov under registration no. NCT01657890.).

Evaluating Surgical Resident Needle Insertion Skill Gains in Central Venous Catheterization Training.

BACKGROUND: Training for ultrasound-guided central venous catheterization (CVC) is typically conducted on static manikin simulators with real-time feedback from a skilled observer. Dynamic haptic robotic trainers (DHRTs) are an alternative method that simulates various patient anatomies and provides consistent feedback for each insertion. This study evaluates CVC needle insertion efficiency and skill gains of both methods. MATERIALS AND METHODS: Fifty-two first-year surgical residents were trained by placing internal jugular (IJ) CVC needles in manikins (n = 26) or robots (n = 26). Manikin-trained participants received verbal feedback from an experienced observer, whereas robotically trained participants received quantitative feedback from the personalized DHRT learning interface. All participants were pretested on a Blue Phantom manikin; participants completed posttesting on a Blue Phantom manikin (n = 26) or a novel manikin (n = 26) with different vessel depth and position. During pretests and posttests residents were timed, motion-tracked, and scored on an IJ CVC checklist. RESULTS: (1) All skills on the IJ CVC checklist showed significant (P < 0.014) improvements from pretests to posttest; (2) Average angle of insertion, path length, and jerk improved significantly (P < 0.005); (3) Average procedural completion time, with standard error (SE) reported, decreased significantly from pretest (M = 3.516 min, SE = 0.277) to posttest (M = 1.997, SE = 0.409). CONCLUSIONS: No significant group differences were observed in overall skill gains, but residents' average procedural completion time decreased significantly from pretests to posttest. Overall results support DHRT as an effective method for training IJ CVC skills.